Most smokers in this country attempt to quit because of concerns about health. However, more than half of those who smoke one pack per day or more fail to quit or even cut back on smoking. Contributing to relapse is the desire to alleviate withdrawal, which has been clearly established and related to nicotine. Withdrawal has two components: somatic and affective. Avoidance of negative affective symptoms is thought to play a bigger role in relapse than avoidance of somatic symptoms, yet little is known about the physiology or specific brain regions that mediate affective components of nicotine withdrawal. The mesolimbic dopamine system is involved in positive reinforcement, but its role in withdrawal is poorly understood. Furthermore, somatic withdrawal in animals cannot be equated with mood in humans. Localizing brain regions involved in withdrawal in humans will provide useful information for understanding mechanisms of and directing therapy aimed at preventing relapse. The training plan outlined in this proposal will give me the skills needed to become an expert in neuroimaging of substance abuse, specifically the effects of nicotine on the brain. I will train under distinguished scientific mentors known for their research on the biology and genetics of nicotinic receptors and behavioral pharmacology of substance abuse. The proposed work represents a qualitatively different phase in my research development that complements the skills I have already acquired in advanced MR neuroimaging techniques. At the end of this training period, I will be able to conduct independent research in neuroimaging of substance abuse. The scientific hypothesis tested by this research is that acute nicotine withdrawal will be associated with changes in cerebral blood flow in mesolimbic dopaminergic brain regions. The hypothesis will be tested using MR arterial spin labeling methods to measure changes in cerebral blood flow (CBF) during acute withdrawal and correlating these changes with mood. Three specific aims are: i) Do CBF measurements provide an in vivo marker for symptoms of acute nicotine withdrawal in smokers? ii) Does acute nicotine withdrawal involve dopaminergic system or non-dopaminergic regions? iii) Does nicotine replacement reverse the alterations in CBF during nicotine withdrawal?